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Molecular Cancer
Published in: Molecular Cancer 1/2004

Open Access 01-12-2004 | Research

Scambio, a novel guanine nucleotide exchange factor for Rho

Authors: Christina Curtis, Bianca Hemmeryckx, Leena Haataja, Dinithi Senadheera, John Groffen, Nora Heisterkamp

Published in: Molecular Cancer | Issue 1/2004

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Abstract

Background

Small GTPases of the Rho family are critical regulators of various cellular functions including actin cytoskeleton organization, activation of kinase cascades and mitogenesis. For this reason, a major objective has been to understand the mechanisms of Rho GTPase regulation. Here, we examine the function of a novel protein, Scambio, which shares homology with the DH-PH domains of several known guanine nucleotide exchange factors for Rho family members.

Results

Scambio is located on human chromosome 14q11.1, encodes a protein of around 181 kDa, and is highly expressed in both heart and skeletal muscle. In contrast to most DH-PH-domain containing proteins, it binds the activated, GTP-bound forms of Rac and Cdc42. However, it fails to associate with V14RhoA. Immunofluorescence studies indicate that Scambio and activated Rac3 colocalize in membrane ruffles at the cell periphery. In accordance with these findings, Scambio does not activate either Rac or Cdc42 but rather, stimulates guanine nucleotide exchange on RhoA and its close relative, RhoC.

Conclusion

Scambio associates with Rac in its activated conformation and functions as a guanine nucleotide exchange factor for Rho.
Appendix
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Literature
1.
Van Aelst L, D'Souza-Schorey C: Rho GTPases and signaling networks. Genes Dev. 1997, 11: 2295-2322.CrossRefPubMed
2.
3.
Teramoto H, Malek RL, Behbahani B, Castellone MD, Lee NH, Gutkind JS: Identification of H-Ras, RhoA, Rac1 and Cdc42 responsive genes. Oncogene. 2003, 22: 2689-2697.CrossRefPubMed
4.
Olson MF, Ashworth A, Hall A: An essential role for Rho, Rac, and Cdc42 GTPases in cell cycle progression through G1. Science. 1995, 269: 1270-1272.CrossRefPubMed
5.
Khosravi-Far R, Solski PA, Clark GJ, Kinch MS, Der CJ: Activation of Rac1, RhoA, and mitogen-activated protein kinases is required for Ras transformation. Mol Cell Biol. 1995, 15: 6443-6453.PubMedCentralPubMed
6.
Lin R, Cerione RA, Manor D: Specific contributions of the small GTPases Rho, Rac, and Cdc42 to Dbl transformation. J Biol Chem. 1999, 274: 23633-23641.CrossRefPubMed
7.
Zohn IM, Campbell SL, Khosravi-Far R, Rossman KL, Der CJ: Rho family proteins and Ras transformation: the RHOad less traveled gets congested. Oncogene. 1998, 17: 1415-1438.CrossRefPubMed
8.
9.
Reuther GW, Lambert QT, Booden MA, Wennerberg K, Becknell B, Marcucci G, Sondek J, Caligiuri MA, Der CJ: Leukemia-associated Rho guanine nucleotide exchange factor, a Dbl family protein found mutated in leukemia, causes transformation by activation of RhoA. J Biol Chem. 2001, 276: 27145-27151.CrossRefPubMed
10.
11.
12.
Haataja L, Groffen J, Heisterkamp N: Characterization of RAC3, a novel member of the Rho family. J Biol Chem. 1997, 272: 20384-20388.CrossRefPubMed
13.
Haataja L, Groffen J, Heisterkamp N: Identification of a novel Rac3-interacting protein C1D. Int J Mol Med. 1998, 1: 665-670.PubMed
14.
Benard V, Bohl BP, Bokoch GM: Characterization of Rac and Cdc42 Activation in Chemoattractant-stimulated Human Neutrophils Using a Novel Assay for Active GTPases. J Biol Chem. 1999, 274: 13198-13204.CrossRefPubMed
15.
16.
Schmidt A, Hall A: Guanine nucleotide exchange factors for Rho GTPases: turning on the switch. Genes Dev. 2002, 16: 1587-1609.CrossRefPubMed
17.
Arai A, Spencer JA, Olson EN: STARS, a striated muscle activator of Rho Signaling and serum response factor-dependent transcription. J Biol Chem. 2002, 277: 24453-24459.CrossRefPubMed
18.
Kaarbo M, Crane DI, Murrell WG: RhoA is highly up-regulated in the process of early heart development of the chick and important for normal embryogenesis. Dev Dyn. 2003, 227: 35-47.CrossRefPubMed
19.
Sah VP, Minamisawa S, Tam SP, Wu TH, Dorn GW, Ross J, Chien KR, Brown JH: Cardiac-specific overexpression of RhoA results in sinus and atrioventricular nodal dysfunction and contractile failure. J Clin Invest. 1999, 103: 1627-1634.PubMedCentralCrossRefPubMed
20.
Wei L, Wang L, Carson JA, Agan JE, Imanaka-Yoshida K, Schwartz RJ: Beta-1 integrin and organized actin filaments facilitate cardiomyocyte-specific RhoA-dependent activation of the skeletal alpha-actin promoter. FASEB J. 2001, 15: 785-796.CrossRefPubMed
21.
Souchet M, Portales-Casamar E, Mazurais D, Schmidt S, Leger I, Javre JL, Robert P, Berrebi-Bertrand I, Bril A, Gout B, Debant A, Calmels TP: Human p63 RhoGEF, a novel RhoA-specific guanine nucleotide exchange factor, is localized in cardiac sarcomere. J Cell Sci. 2002, 115 (Pt 3): 629-640.PubMed
22.
Aoki H, Izumo S, Sadoshima J: Angiotensin II activates RhoA in cardiac myocytes: a critical role of RhoA in angiotensin II-induced premyofibril formation. Circ Res. 1998, 82: 666-676.CrossRefPubMed
23.
Horii Y, Beeler JF, Sakaguchi K, Tachibana M, Miki T: A novel oncogene, ost, encodes a guanine nucleotide exchange factor that potentially links Rho and Rac signaling pathways. EMBO J. 1994, 13: 4776-4786.PubMedCentralPubMed
24.
Ren Y, Li R, Zheng Y, Busch H: Cloning and characterization of GEF-H1, a microtubule-associated guanine nucleotide exchange factor for Rac and Rho GTPases. J Biol Chem. 1998, 273: 34954-34960.CrossRefPubMed
25.
Krendel K, Zenke FT, Bokoch GM: Nucleotide exchange factor GEF-H1 mediates cross-talk between microtubules and the actin cytoskeleton. Nat Cell Biol. 2002, 4: 294-301.CrossRefPubMed
26.
Glaven JA, Whitehead I, Bagrodia S, Kay R, Cerione RA: The Dbl-related protein, Lfc, localises to microtubules and mediates the activation of Rac signaling pathways in cells. J Biol Chem. 1999, 274: 2279-2285.CrossRefPubMed
27.
Vanni C, Mancini P, Gao Y, Ottaviano C, Guo F, Salani B, Torrisi MR, Zheng Y, Eva A: Regulation of proto-Dbl by intracellular membrane targeting and protein stability. J Biol Chem. 2002, 277: 19745-19753.CrossRefPubMed
28.
Han J, Das B, Wei W, Van Aelst L, Mosteller RD, Khosravi-Far , Westwick JK, Der CJ, Broek D: Lck regulates Vav activation of members of the Rho family of GTPases. Mol Cell Biol. 1997, 17: 1346-1353.PubMedCentralPubMed
29.
Aghazadeh B, Lowry WE, Huang XY, Rosen MK: Structure basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylation. Cell. 2000, 102: 625-633.CrossRefPubMed
30.
Heisterkamp N, Groffen J: Philadelphia-positive leukemia: a personal perspective. Oncogene. 2002, 21: 8536-8540.CrossRefPubMed
31.
Ciano-Oliveira CD, Sirokmany G, Szaszi K, Arthur WT, Masszi A, Peterson M, Rotstein OD, Kapus A: Hyperosmotic stress activates Rho: differential involvement in Rho kinase-dependent MLC phosphorylation and NKCC activation. Am J Physiol Cell Physiol. 2003, 285: C555-C566.CrossRefPubMed
32.
Senadheera D, Haataja L, Groffen J, Heisterkamp N: The small GTPase Rac interacts with ubiquitination complex proteins Cullin-1 and CDC23. Int J Mol Med. 2001, 8: 127-133.PubMed
33.
Rudert F, Visser E, Gradl G, Grandison P, Shemshedini L, Wang Y, Grierson A, Watson J: pLEF, a novel vector for expression of glutathione S-transferase fusion proteins in mammalian cells. Gene. 1996, 169: 281-282.CrossRefPubMed
Metadata
Title
Scambio, a novel guanine nucleotide exchange factor for Rho
Authors
Christina Curtis
Bianca Hemmeryckx
Leena Haataja
Dinithi Senadheera
John Groffen
Nora Heisterkamp
Publication date
01-12-2004
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2004
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-3-10

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